Antidiarrheal compositions and use thereof

ABSTRACT

Antidiarrheal compositions showing enhanced antidiarrheal activity comprise a non-steroidal anti-inflammatory drug compound and a polymeric hydroabsorptive agent. A patient in need of remedial or preventive treatment of diarrhea symptoms is administered an antidiarrheally effective amount of said antidiarrheal compositions.

FIELD OF THE INVENTION

This invention relates to antidiarrheal compositions of enhancedantidiarrheal activity and to the use thereof to treat a patient in needof preventative or remedial treatment of diarrhea symptoms.

BACKGROUND OF THE INVENTION

Diarrhea can result from a variety of pathophysiological disordersincluding bacterial and parasitic infections, disease or debilitation oforgans such as liver, adrenal and others. It can also occur as a resultof other therapy or diet. In all cases, diarrhea is generally a symptomof organic gastrointestinal disorders and not itself a disorder. Chronicdiarrhea is generally due to intestinal hypermotility and rapidtransport. It may also be due to, or accompanied by hypersecretion ofacid gastric juices or decreased reabsorption and may, in someinstances, particularly those accompanied by hypersecretion, beassocited with emotional tension and psychological conflicts.

Antidiarrheal compounds are, of course, well-known in the medicinal artsand take varous forms. In particular there are a variety of productsknown which act systemically to provide antidiarrheal effects whenadministered in a manner which will enable the drug to be taken into thesystem at effective therapeutic levels.

It is becoming increasingly evident from the literature thatnon-steroidal anti-inflammatory drugs (NSAID) are effectiveantidiarrheal agents, but generally, only at high doses. It would behighly desirable, however, if the antidiarrheal doses of the NSAID weremuch lower than those typically reported for their anti-inflammatory oranalgesic activity and the antidiarrheal activity of these NSAID couldbe potentiated so as to provide more effective antidiarrheal activity.

SUMMARY OF THE INVENTION

Antidiarrheal compositions of enhanced antidiarrheal activity areprovided by compositions of a NSAID and a polymeric hydroabsorptiveagent. Administration of an antidiarrheally effective amount of saidcompositions to patients would provide remedial or preventive treatmentof diarrhea symptoms.

DETAILED OF THE INVENTION

The antidiarrheal activity of NSAID compounds has been found to beunexpectedly potentiated when administered concurrently with a polymerichydroabsorptive agent. Preferred hydroabsorptive agents are nonionicpolymeric hydroabsorptive agents and still more preferredhydroabsorptive agents are psyllium and glucomannan. Especiallypreferred is psyllium.

Psyllium (plantago seed) useful in the compositions of this invention isdescribed in Pharmacopeia XX, page 634, U.S. Pharmacopeial Convention,Inc., 1980. Glucomannan useful in the compositions of this invention isdescribed in the article titled "Japanese Diet Food" on page 22 of theSeptember 1980 issue of Food Engineering. Glucomannan is a hydrophilichemicellulose extract from the konjac root and is sold as an appetitecurb under the trademark Regal Mannan by Regal Vitamin Co., Costa Mesa,California.

The NSAID compounds whose antidiarrheal activity is potentiated by apolymeric hydroabsorptive agent of this invention vary widely in theirchemical structure and in their biological profiles as analgesics,anti-inflammatory agents and antipyretic agents. Among the classes ofNSAID compounds found useful in the compositions of this invention theremay be mentioned for example, salicylic acid derivatives, propionic acidderivatives, indole and pyrole acetic acid derivatives, pyrazolederivatives, fenamate derivatives, oxicam derivatives, phenylacetamidederivatives and the like. Among the members of this group of NSAIDcompounds there may be mentioned for example, aspirin, salsalate, sodiumsalicylate, magnesium salicylate, acetaminophen, phenacetin, diflunisal,zomepirac sodium, ibuprofen, naproxen, fenoprofen calcium, piroxicam,flurbiprofen, mefenamic acid, sulindac, fenbufen, ketoprofen, tolmetinsodium, indomethacin, meclofenamate sodium, phenylbutazone, and thelike.

Especially preferred NSAID compounds in the antidiarrheal compositionsof this invention are aspirin, indomethacin and ibuprofen.

While this invention envisions any antidiarrheally effectivepotentiating combination of NSAID compound and polymeric hydroabsorptiveagents, the relative amounts of NSAID compound to polymerichydroabsorptive agent in the compositions of this invention that providethe enhanced antidiarrheal activity is in the range of ratio of NSAIDcompound to polymeric hydroabsorptive agent of from about 1:30 to about1:600, more preferably from about 1:75 to about 1:400 and mostpreferably from about 1:100 to about 1:200.

The compositions of the present invention can be prepared in formssuitable for administration to humans and animals by compounding aneffective single dose amount of the composition of the activeingredients of this invention with known ingredients generally employedin the preparation of therapeutic compositions provided as tablets,capsules, lozenges, chewable lozenges, pills, powder, granules,suspensions, or other similar forms which can be taken orally. Ingeneral the composition of the active ingredients of this inventionabove are indicated for use as pharmacotherapeutic agents in a widevariety of mammalian conditions which require relief of diarrheasymptoms accompanying abnormal action of the gastrointestinal system.

The dosage regimens in carrying out the pharmacotherapeutic methodsutilizing the compositions of this invention are those which insuremaximum therapeutic response until improvement is obtained andthereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of diarrhea. In general, the single oral dose may contain upto the usual therapeutic limit of the individual NSAID in combinationwith the appropriate amount of polymeric hydroabsorptive agent toachieve the appropriate ratios. For example, at the 1:30 ratio, 400 mgibuprofen might be combined with 12 g polymer whereas 50 mg indomethacinmight be combined with 1.5 g polymer. At the other extreme, at anNSAID/polymer ratio of about 1:600, as little as 1 mg ibuprofen plus 600mg polymer might be an effective dose. The preferred dose levels wouldbe those that achieve optimal clinical antidiarrheal effectiveness atthe lowest NSAID dose. The NSAID compound and the polymerichydroabsorptive agent may be administered concurrently or together as asingle formulation. Fractional or multiple doses can of course be givenbearing in mind that in selecting the appropriate dosage in any specificcase, consideration must be given to the patient's weight, generalhealth, age, and other factors which may influence response to the drug.The drug response on oral administration usually follows within thefirst hour after administration and may be maintained for up to about 4hours. The drug is generally given in single doses up to 8 times dailyor as required to maintain effective continuous relief of diarrheasymptoms.

Compositions intended for oral use may be prepared according to methodsknown generally in the art. Such compositions may contain one or moreagents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide a pharmaceutically elegant and palatable preparation. Orally,they may be administered in tablets, lozenges, oily suspensions,dispersible powders or granules, or hard or soft capsules which containthe active ingredients in admixture with non-toxic pharmaceuticallyacceptable excipients. Excipients which may be, for example, inertdiluents, such as calcium carbonate, magnesium carbonate, calciumphosphate, calcium sulphate, lactose, cellulose, microcrystallinecellulose, starch, modified starch, dextrose, sucrose, mannitol,sorbitol; binding agents, for example, polyvinyl pyrrolidone, celluloseethers such as sodium carboxymethylcellulose, methyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxy ethylcellulose and ethyl cellulose, natural gums such as acacia, tragacanth,pectin, guar and karaya, gelatin, alginates, starch, modified starch,polyethylene glycol, microcrystalline cellulose, sugars such as sucrose,sorbitol and glucose, corn syrups, polyvinyl alcohols, polyacrylamides,or polyvinyloxoazolidone; disintegrants, such as, cross linked polyvinylpyrrolidone, sodium starch glycollate, cross-linked carboxymethylcellulose, ion exchange resins, starch, modified starches,microcrystalline cellulose, cellulose, cellulose derivatives, alginates,alginic acid or clays; lubricants, glidants and anti-adherants, such asfor example, silicone fluids, hydrogenated vegetable oils, light mineraloil, microfine silicas, metallic stearates, stearic acid, polyethyleneglycol, talc, corn starch, sodium benzoate, sodium acetate,polyoxyethylene monostearate, magnesium carbonate or magnesium oxide.The tablets may be uncoated or they may be coated by known techniques tomake them more effective, to delay disintegration or absorption or tomake them more palatable or for other reasons for which orallyadministered drugs have been previously provided in coated form.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent,binding agent, disintegrant, lubricant, glidant or anti-adherent asdescribed hereinbefore for tablets, or as soft gelatin capsules whereinthe active ingredient is mixed with an oil medium, for example, arachisoil, liquid paraffin or olive oil.

Oily suspensions may be formulated by suspending the composition of theactive ingredients in a vegetable oil, for example, arachis oil, oliveoil, sesame oil or coconut oil, or in a mineral oil, such as liquidparaffin. The oil suspensions may contain a thickening agent, forexample, beeswax, hard paraffin or cetyl alcohol. Sweetening agents,such as those set forth above, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredients inadmixture with dispersing, wetting agent or suspending agents. Theseexcipients are suspending agents, for example, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidine, gum tragacanth and gum acacia; dispersing orwetting agents may be a naturally occurring phosphatide, for example,lecithin; or condensation products or an alkylene oxide with fattyacids, for example, polyoxyethylene stearate; or condensation productsof ethylene oxide with long-chain aliphatic alcohols, for example,heptadecaethyleneoxy-cetanol; or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, for example,polyoxyethylene sorbitol mono-oleate; or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example, polyoxyethylene sorbitan mono-oleate. They mayalso include one or more preservatives, for example, ethyl, or n-propyl,p-hydroxy benzoate, one or more coloring agents, one or more flavoringagents, and one or more sweetening agents, such as sucrose.

Generally, these compositions may be tableted or otherwise formulatedfor oral use so that for every 100 parts by weight of the composition,there are present between 5 and 95 parts by weight of the activeingredients.

The enhanced antidiarrheal activity for the compositions of thisinvention was shown by a castor oil-induced diarrheal test in rats whichis a modified test described by Niemegeers et al., Arzneim-Forsch 22,516-518 (1972). The modified test was as follows. An NSAID compound,such as aspirin (ASA), indomethacin (I) or Ibuprofen (IBF) and apolymeric hydroabsorptive agent, such as psyllium (PS) or glucomannan(GM) were evaluated alone and in NSAID/polymeric agent ratios of 1:75,1:200, 1:400 and 1:600. The test materials were suspended in 0.25%methocellulose and administered to groups of 10 to 45 fasted rats viaoral intubation. One hour following treatment, each rat was given 1.0 mlof castor oil via intubation and placed into an individual cage linedwith absorbent paper. The papers were examined and replaced hourly up to6 hours following the castor oil challenge. Antidiarrheal activity wasexpressed quantally as an "all-or-none response"; once an animaldemonstrated evidence of diarrhea, that animal was considered to beunprotected at all subsequent time points.

Median effective antidiarrheal doses (ED₅₀ 's) were determined hourlyfor up to six hours post-treatment for the individual ingredients andfor the combinations on the basis of the dose response data generated inthe aforementioned test regimen. Drug interactions were evaluatedaccording to the model proposed by Finney, Probit Analysis, CambridgeUniv. Press, 3rd Edition (1971) and Bliss, Ann. Appl. Biol., 26, pp585-615 (1939). When the slopes of the dose-response data for theindividual drugs and their combination were parallel, the data wereanalyzed according to the model of simple similar action. In those caseswhere significant non-parallelism occurred, the data were analyzedaccording to the model of independent joint action.

Results

The ED₅₀ 's of the individual drugs and the actual and predicted ED₅₀ 'sof the combinations are tabulated below; except where indicated, thedata were analyzed according to the model of simple similar action:

    __________________________________________________________________________    ED.sub.50 Values (mg/kg)                                                                              Predicted                                                           Actual (NSAID +                                                                         NSAID +   Relative                                    Combination                                                                           Ratio Polymer)  Polymer   Potency                                     __________________________________________________________________________    IBF/PS  Individual                                                                          IBF  PS                                                         (1 hour)                                                                              Drugs 6.9  293  --        --                                                  1:75  113(1.5 + 112)                                                                          191(2.5 + 188)                                                                          1.69                                                1:200 147(0.7 + 146)                                                                          243(1.2 + 241)                                                                          1.65                                                1:400 162(0.4 + 162)                                                                          266(0.7 + 265)                                                                          1.64                                        IBF/PS  Individual                                                                          IBF  PS                                                         (2 hour)                                                                              Drugs 51   1055 --        --                                                  1:400 539(1.3 + 538)                                                                          1003(2.5 + 1000)                                                                        1.86                                        IBF/GM.sup.1                                                                          Individual                                                                          IBS  GM                                                         (1 hour)                                                                              Drugs 6.9  225  --        --                                                  1:600 162(0.3 + 162)                                                                          225(0.4 + 224)                                                                          1.39                                        ASA/PS  Individual                                                                          ASA  PS                                                         (1 hour)                                                                              Drugs 3.0  298  --        --                                                  1:75  102(1.3 + 101)                                                                          131(1.7 + 129)                                                                          1.28                                                1:200 129(0.6 + 128)                                                                          201(1.0 + 200)                                                                          1.56                                        I/PS    Individual                                                                          I    PS                                                         (1 hour)                                                                              Drugs 0.44 447  --        --                                                  1:400 30(0.07 + 29.93)                                                                        125(0.31 + 124.7)                                                                       4.22                                        I/PS    Individual                                                                          I    PS                                                         (2 hour)                                                                              Drugs 6.29 1076 --        --                                                  1:400 353(0.88 + 352.1)                                                                       741(1.85 + 739.2)                                                                       2.14                                        I/PS    Individual                                                                          I    PS                                                         (4 hour)                                                                              Drugs 24.67                                                                              10413                                                                              --        --                                                  1:400 1184(2.95 + 1181)                                                                       5091(12.7 + 5078)                                                                       4.29                                        __________________________________________________________________________     .sup.1 Because of significant nonparallelism, the data did not fit the        model of simple similar action and were analyzed for independent joint        action.                                                                  

Based on the relative potency of the actual value to the predictedvalues, significant enhancement of activity was found withibuprofen/psyllium ratios of 1:75, 1:200 and 1:400. The activity of thecombinations at 1 hour was 64-69% greater than expected on the basis ofthe individual components. At 2 hours, the activity of the 1:400 ratiowas 86% greater than expected. The interaction for ibuprofen andpsyllium at 1 hour post challenge is demonstrated by data in Loeweisobolograms (S. Loewe: Pharm. Rev. 9:237-242, 1957) in the drawing. Inthe drawing, the diagonal line joining the ED₅₀ values of the two drugsgiven separately represents simple additivity of drug effects. Thedashed lines on each side of the diagonal line give the 95% confidencelimits for this line of additivity. ED₅₀ 's of combinations fallingunder the curve (between the lower dashed line and the origin) indicatepotentiation (unexpected enhancement) of effects while those above theupper dashed line would suggest antagonism between the two drugs. Thefour diagonal lines radiating from the origin represent the dose ratiosof ibuprofen to psyllium used in rats receiving the combined drugdosages. The horizontal and vertical bars through each ED₅₀ point arethe 95% confidence limits. The visual estimates from the isobologram ofthe drawing indicate that in the method of the invention compositionshaving a ratio of a NSAID compound, such as ibuprofen to a polymerichydroabsorptive agent, such as psyllium, of from about 1:30 to greaterthan 1:400 give unexpectedly enhanced activity.

The relative potency data in the hereinbefore set forth table shows thatthe combination of indomethacin with hydroabsorptive polymer psylliumwas up to four times more active than predicted based on addition of theactivities of indomethacin and psyllium at 1, 2 and 4 hours. Also theactivity of the combination of ibuprofen and glucomannan was 37% greaterthan expected based on the activities of the individual components andthe activity of the combination of aspirin and psyllium was from 28 to56% greater than expected based on the activities of the individualcomponents.

We claim:
 1. An antidiarrheal composition comprising an antidiarrhealeffective amount of a non-steroidal antiinflammatory propionic acidderivative selected from the group consisting of ibuprofen, naproxen,fenoprofen calcium, flurbiprofen, fenbufen and ketoprofen, and anonionic polymeric hydroabsorptive agent selected from the groupconsisting of psyllium and glucomannan wherein the weight ratio of saidpropionic acid derivative to said hydroabsorptive agent is in the rangeof from about 1:30 to about 1:600.
 2. An antidiarrheal compositioncomprising an antidiarrheal effective amount of ibuprofen and a nonionicpolymeric hydroabsorptive agent selected from the group consisting ofpsyllium and glucomannan wherein the weight ratio of said ibuprofen tosaid hydroabsorptive agent is in the range of from about 1:30 to about1:600.
 3. A composition of claim 2 wherein the hydroabsorptive agent ispsyllium.
 4. A composition of claim 3 wherein the weight ratio ofibuprofen to psyllium is about 1:75 to about 1:400.
 5. A composition ofclaim 2 wherein the hydroabsorptive agent is glucomannan.
 6. Acomposition of claim 5 wherein the weight ratio of ibuprofen toglucomannan is about 1:75 to about 1:400.
 7. A method for the remedialor preventive treatment of diarrheal symptoms comprising concurrentlyadministering to a host in need thereof an antidiarrheal effectiveamount of a non-steroidal antiinflammatory propionic acid derivativeselected from the group consisting of ibuprofen, naproxen, fenprofencalcium, flurbiprofen, fenbufen and ketoprofen, and a nonionic polymerichydroabsorptive agent selected from the group consisting of psyllium andglucomannan wherein the weight ratio of said propionic acid derivativeto said hydroabsorptive agent is in the range of from about 1:30 toabout 1:600.
 8. A method for the remedial or preventive treatment ofdiarrhea symptoms comprising concurrently administering to a host inneed thereof an antidiarrheal effective amount of ibuprofen and anonionic polymeric hydroabsorptive agent selected from the groupconsisting of psyllium and glucomannan wherein the weight ratio of saidibuprofen to said hydroabsorptive agent is in the range of from about1:30 to about 1:600.
 9. A method for remedial or preventive treatment ofdiarrhea symptoms comprising administering to a host in need thereof anantidiarrheal effective amount of a composition of claim
 3. 10. A methodfor remedial or preventive treatment of diarrhea symptoms comprisingadministering to a host in need thereof an antidiarrheal effectiveamount of a composition of claim
 5. 11. A method for remedial orpreventive treatment of diarrhea symptoms comprising administering to ahost in need thereof an antidiarrheal effective amount of a compositionof claim
 4. 12. A method for remedial or preventive treatment ofdiarrhea symptoms comprising administering to a host in need thereof anantidiarrheal effective amount of a composition of claim 6.